Nuclear hormone receptors make up a family of ligand-inducible transcription factors whose members are involved in multiple physiological and developmental functions. During the last 20 years, more than sixty structurally and functionally related proteins belonging to this family have been identified. Nuclear hormone receptor family includes, in addition to classical steroid receptors (estrogen receptor, progesterone receptor, androgen receptor, glucocorticoid receptor and mineralo-corticoid receptor) also receptors e.g. for thyroid hormone, vitamin D and retinoids. Furthermore, a subclass of so-called orphan receptors for which no ligands have been identified up to date belong to this protein family. See Mangelsdorf et al, Cell (1995) 83(6): 835-839 and references therein. There exists an intense research directed to identify novel modulators for these proteins, ultimate goal thus being to find new therapies and treatment options for conditions and diseases modulated by nuclear/steroid receptors.
Steroidal androgens have been used for decades in the treatment of diseases resulting from deficiency in androgen action. They have also received attention for their use as hormone replacement therapy of aging men and in regulation of male fertility. However, current steroidal androgens, such as synthesized testosterone and its derivatives, have severe limitations. Testosterone is rapidly degraded by the liver and thus has a low systemic bioavailability after oral administration. Further, orally available testosterone formulations, e.g. methyltestosterone, have been associated with alterations in liver function. Various other attempts have been made to overcome these drawbacks of steroidal androgens as therapeutic agents, but with limited success. Current testosterone formulations used in clinical practice include e.g. injections, patches and gels.
In recent years, there has been growing interest in the development of nonsteroidal modulators for steroid receptors for therapeutical use. It has been shown that nonsteroidal ligands can achieve better receptor selectivity and better physicochemical, pharmacokinetic and pharmacological properties. For androgen receptor (AR), nonsteroidal antagonists (antiandrogens) are now used clinically to counteract the undesirable actions of excessive androgens. In contrast, nonsteroidal AR agonists, which would have potential in the treatment of diseases resulting from androgen deficiency, have just recently been reported. Still, the structural elements of nonsteroidal ligands that would lead to optimal agonist activity and tissue selectivity are poorly defined.
Non-steroidal propionanilides having androgen receptor modulating activity have been described e.g. in patent publications EP 100172, EP 253503, WO 98/53826 and WO 02/16310. The design of propionanilide structured AR modulators has concentrated on compounds where the anilide ring is substituted by two electron-withdrawing substituents such as halogen, cyano, trifluoromethyl or nitro, since such substitution has been reported to enhance the androgen receptor binding affinity of the ligand. See e.g. Tucker, H. et al., J. Med. Chem., 1988, 31, 954-959.